EP2200603B1 - Osmolyte zur behandlung von allergisch bedingten atemwegserkrankungen - Google Patents

Osmolyte zur behandlung von allergisch bedingten atemwegserkrankungen Download PDF

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Publication number
EP2200603B1
EP2200603B1 EP08801690A EP08801690A EP2200603B1 EP 2200603 B1 EP2200603 B1 EP 2200603B1 EP 08801690 A EP08801690 A EP 08801690A EP 08801690 A EP08801690 A EP 08801690A EP 2200603 B1 EP2200603 B1 EP 2200603B1
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EP
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Prior art keywords
medicament
use according
treatment
osmolytes
allergic
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EP08801690A
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German (de)
English (en)
French (fr)
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EP2200603A2 (de
Inventor
Jean Krutmann
Georg Lentzen
Thomas Schwarz
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Bitop AG
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Bitop AG
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Priority to DK11004754.5T priority Critical patent/DK2380569T3/da
Priority to PL08801690T priority patent/PL2200603T3/pl
Priority to PL15189573T priority patent/PL3006022T3/pl
Priority to EP15189573.7A priority patent/EP3006022B1/de
Priority to PL11004754T priority patent/PL2380569T3/pl
Application filed by Bitop AG filed Critical Bitop AG
Priority to EP18203610.3A priority patent/EP3482755A1/de
Priority to EP11004754.5A priority patent/EP2380569B1/de
Publication of EP2200603A2 publication Critical patent/EP2200603A2/de
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Publication of EP2200603B1 publication Critical patent/EP2200603B1/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • Osmolytes of extremophilic microorganisms form a known group of low molecular weight protective substances. Extremophiles are very unusual microorganisms, as they grow optimally eg at high salt concentrations (up to 200 g NaCl / I) and high temperatures (60-110 ° C), which would lead to massive damage of cellular structures in mesophilic ("normal") organisms. In recent years, therefore, much research has been done to identify the biochemical components that lead to the remarkable thermal, chemical and physical stabilization of cell structures. Although many enzymes from hyperthermophilic microorganisms are stable even under high temperatures, this is not generally true for the cellular structures of thermo- and hyperthermophilic organisms.
  • osmolytes (compatible solutes) found in extremophilic microorganisms are not produced by human or animal cells.
  • This inflammation is a defense reaction of the organism and its tissues against harmful stimuli with the aim of remedying the damage, or at least locally limiting and eliminating the cause of the damage (eg invading bacteria or foreign bodies).
  • Inflammation can be triggered by microorganisms (bacteria, viruses, fungi or parasites), foreign bodies (pollen, asbestos or silicate crystals), tissue destruction by mechanical damage, chemical noxae and physical influences as well as by the body's own triggers (disintegrating tumor cells, extravasal blood, autoimmune reactions) or crystals of substances precipitated in the body (uric acid, calcium oxalate and phosphate, cholesterol).
  • the action of the noxae in the body leads to the release of inflammatory mediators in the body with the help of helper T cells, in particular histamine and interieukin-8, leukotrienes and tumor necrosis factor-alpha (TNF-alpha), which activates the downstream cascade of anti-inflammatory action in the body becomes.
  • helper T cells in particular histamine and interieukin-8, leukotrienes and tumor necrosis factor-alpha (TNF-alpha)
  • TNF-alpha tumor necrosis factor-alpha
  • the strain expresses the ICAM-1 molecule more strongly in the affected cells.
  • Respiratory allergens cause reactions in the respiratory tract, typically with mucosal edema and hypersecretion (allergic rhinitis, hay fever) and bronchospasm (asthma). Food allergens, however, primarily gastrointestinal symptoms such as nausea, vomiting and diarrhea. The skin reacts to allergens with itching, swelling and hives (urticaria) as well as atopic dermatitis (atopic dermatitis). On the other hand, if the allergen gets directly into the bloodstream (eg infusion of blood products, medicines) or if the allergen exposure is particularly strong, a systemic immediate reaction results, which may lead to a life-threatening drop in blood pressure (anaphylactic shock).
  • the treatment of acute and / or chronic inflammations of the nasal cavity and / or paranasal sinuses is carried out primarily with decongestant nasal sprays, cortisone-containing nasal sprays, expectorants or antibiotics. All mentioned substances are burdened with side effects. Cortisone-containing nasal sprays often trigger allergic reactions themselves.
  • allergic rhinitis rhinoconjunctivitis
  • rhinoconjunctivitis rhinoconjunctivitis
  • Change of level ie from the relatively harmless rhinitis develops the very serious bronchial asthma.
  • it is essential to already treat allergic rhinoconjunctivitis sufficiently and intensively or to prevent it. Only then can patients live without complications and only then can a possibly life-threatening floor change be prevented.
  • corticosteroids are most effective in controlling the inflammation underlying rhinoconjunctivitis.
  • Antihistamines are used in the acute phase of allergic rhinoconjunctivitis to relieve the often distressing symptoms.
  • the systemic administration of antistaminics has sedating side effects (malnutrition, fatigue), which significantly limit the use.
  • the new generation drugs have significantly fewer side effects, they also have a much worse effect in many cases.
  • osmolytes such as eg ectoine
  • a form which is to be administered nasally for example, is advantageous for the prophylaxis and treatment of "rhinits allergica (hay fever)".
  • the rationale is based on the observation that in the epithelial cells in the inflammatory reaction typical of rhinitis allergica (hay fever), the interaction of the epithelial cells with the relevant allergen (eg pollen) leads to an upregulation of adhesion molecules such as ICAM -1, comes in these cells, which is the prerequisite for the formation of the clinical symptoms of the cold.
  • the inventors have observed that the upregulation of ICAM-1 can be inhibited by ectoin by proinflammatory stimuli.
  • an osmolyte-containing nasal administration form for the treatment and prophylaxis of hay fever can be used. Because of exclusively water-structure-altering physical effect of osmolytes is practically impossible to expect the typical steroid-specific side effects.
  • topical administration with the aid of a nasal spray on the nasal epithelia is advantageous for various reasons.
  • the administration can take place simultaneously, sequentially or separately.
  • Topical administration of the osmolyte-containing nasal spray quickly eliminates the acute symptoms (eg, irritation, itching, swelling) without the side effects.
  • the osmolyte contained in the preparation the underlying inflammation of the disease can be successfully controlled.
  • the treating physician in borderline cases can not determine with complete certainty whether "only" rhinoconjunctivitis or already a respiratory disease, such as asthma
  • bronchiale is present. It is advantageous that the combination according to the invention can also be used for the treatment of diseases of the upper and lower respiratory tract.
  • osmolytes could be used in combination with other active principles and thus reduce the necessary use concentration of the other substance.
  • Another possibility would be the preventive administration of osmolytes, which directly weaken the side effect profile of the substances to be added later. This makes the general combination of extremes with steroids interesting.
  • a combination therapy of osmolytes (especially ectoine and hydroxyectoine) with other intranasally or intraocularly administered drugs that cause unwanted side effects makes sense.
  • osmolyte drug formulations that are administered nasally or ocularly to treat an organ disease (e.g., cancer) but have an inflammatory side effect on the nasal epithelium.
  • organ disease e.g., cancer
  • Glucocorticoids or antihistamines or the preventive administration of osmolytes prior to treatment with these substances could be a general principle in other forms of administration (topical, dermal, intraperitoneal, intravenous, intramuscular, oral) an effective way to reduce or reduce the side effects of the substances the combination of the active principles of osmolytes with those of the simultaneously or subsequently applied active ingredients to reduce the use concentration of the active ingredients, resulting in a low burden on the treated patient.
  • the compatible solutes are preferably ectoine, 4,5,6,7-tetrahydro-2-methyl-1H- [1,3] -diazepine-4-S-carboxylic acid (homoectin), hydroxyectoine, di -myo inositol phosphate (DIP), cyclic 2,3-diphosphoglycerate (cDPG), 1,1-di-glycerol phosphate (DGP), ⁇ -mannosylglycerate (firoin), ⁇ -mannosylglyceramide (Firoin-A), di-mannosyl-di inositol phosphate (DMIP), glucosylglycerol, taurine, betaine, citrulline and / or a derivative thereof Compounds such as salts, esters or acids.
  • the concentration of the compatible solutes is typically between 0.01 and 20 wt .-%, preferably between 0.1 and 10 w
  • the effective concentrations can be achieved even at low dosages.
  • the gift of the osmolyte allows the fight against the annoying reactions such as itching, nasal flow and prevents the progression of inflammation. Thus, a better compliance of the patients is to be expected.
  • the present invention is therefore based on the object of providing agents for the prevention or treatment of immunological hypersensitivity reactions, in particular allergic rhinitis, which represent a broader (deliberately non-monospecific), low-side-effects and thus a more effective therapeutic approach.
  • One aspect of the present invention is the use of osmolytes for the manufacture of a medicament or medical device, e.g.
  • pro-inflammatory gene products e.g., ICAM1
  • ICAM1 pro-inflammatory gene products
  • the dosage may be several times a day, with the single dose depending on the osmolyte used, and more particularly on the general condition of the patient (age, weight, etc.) and the severity of the disease.
  • formulations for example nasal sprays, nasal drops and eye drops, in question come. Due to the water solubility of the active ingredient osmolyte (preferably ectoine), formulations containing these active ingredients can preferably be formulated as aqueous solutions.
  • active ingredient osmolyte preferably ectoine
  • the pharmaceutical compositions of the invention may contain other ingredients such as preservatives, stabilizers, isotonizing agents, thickeners, suspension stabilizers, pH adjusters, buffer systems and wetting agents.
  • the pharmaceutical compositions of the invention may also contain other active ingredients such as antihistamines or steroidal agents (eg, loteprednol etabonate).
  • Suitable preservatives are: benzalkonium chloride, chlorobutanol, thiomersal, methylparaben, propylparaben, sorbic acid and its salts, sodium edetate, phenylethyl alcohol, chlohexidine hydrochloride acetate, digluconate, cetylpyridinium chloride, bromide, chlorocresol, phenylmercuric acetate, phenylmercuric nitrate, phenylmercuric borate, phenoxyethanol.
  • Suitable adjuvants for adjusting the isotonicity of the formulations are, for example: sodium chloride, potassium chloride, mannitol, glucose, sorbitol, glycerol, propylene glycol. In general, these adjuvants are used in concentrations of 0.1 to 10%.
  • the formulations of the invention may also include suitable buffering or other pH adjuvant adjuvants to adjust and maintain a pH of the order of 4-8, preferably from 5 to 7.5.
  • suitable buffer systems are citrate, phosphate, tromethamol, glycine, borate, acetate. These buffer systems can be prepared from substances such as citric acid, monosodium phosphate, disodium phosphate, glycine, boric acid, sodium tetraborate, acetic acid or sodium lactate.
  • Suitable wetting agents for the formulations are: benzalkonium chloride, cetylpyridinium chloride, tyloxapol, various polysorbates [Tween (TM) ] as well as other polyoxyethylated substances and poloxamers.
  • a suitable agitator container about 45 kg of purified water submit. Therein add the active ingredient ectoine, hydroxypropylmethylcellulose, sodium acetate, benzalkonium chloride and sorbitol solution in succession and dissolve with stirring. Fill the resulting solution with purified water to a volume of 49.5 liters. Adjust the pH of the solution to pH 6.0 with 1 N sodium hydroxide solution. Make up to the final volume of 50.0 liters with purified water and stir. Filter the solution through a suitable filter and fill into bottles, which are then fitted with a suitable nasal spray pump.
  • OVA ovalbumin
  • mice were treated with ovalbumin aerosol on day 28 and day 38 for 30 minutes each treated by inhalation.
  • the mice were placed in a Plexiglas chamber.
  • a 1% OVA solution was added via an inhaler nebulized.
  • the animals are anesthetized by means of a mixture of ketamine and Rompun. 50 ⁇ l of a sterile ectoine solution or 0.9% saline solution was then applied by glass capillary to the nostril until it was completely inhaled. The total of 14 treatments started on day 0. The last treatment was on day 32.
  • the endpoints of the study were bronchial hyperreactivity using plethysmograph, the cellular composition of bronchoalveolar lavage (BAL), and the release of OVA-specific IgE and IgG1 antibodies.
  • the animals were then anesthetized, gently intubated orotracheally and after laying an esophageal catheter and reaching a steady state, first the lung function before provocation bodyplethysmographically measured (including parameters such as tidal volume, respiratory rate, dynamic compliance and lung resistance).
  • the data storage and evaluation was carried out with a computer program specially developed for these lung function tests (HEM, Notocord / France). This is followed by a defined inhalative exposure of the experimental animals to the allergen ovalbumin (ovalbumin challenge, model of an allergically induced asthmatic reaction).
  • the late allergic phase was studied 24 h after ovalbumin challenge.
  • the animals were examined for airway hyperreactivity to nonspecific stimuli.
  • a hyperreactivity test was carried out in the form of a gradually increasing inhaled acetylcholine provocation.
  • the animals were killed painlessly and the lungs lavaged (BAL). From the lavage fluid, the total cell count and the differential cell image including the number of eosinophils in the BAL was determined.
  • the patients were stimulated intranasally with a defined allergen and the allergic reaction was measured using various parameters. Thereafter, a 2-week treatment with ectoine nasal spray or placebo nasal spray (0.9% NaCl) was carried out and a renewed stimulation with the defined allergen together with measurement of the allergic reaction was carried out.
  • the patients were crossoverally treated analogously with the ectoin nasal spray or placebo nasal spray.
  • ICAM-1 The expression of ICAM-1 was measured by differential reverse transcriptase PCR (RT-PCR) and the Applied Biosystem kit. To account for the normal variations in skin cell gene expression, ICAM-1 expression is related to the constitutively formed housekeeping gene ⁇ -actin. Semiquantitative analysis of RT-PCR was performed by ion exchange chromatography with a UV spectrophotometer (A260).
  • the UVA radiation induces an upregulation of ICAM-1 expression.
  • Pretreatment of keratinocytes with 1mM ectoine can almost completely abolish UVA-induced ICAM-1 induction at all times.

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  • Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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EP08801690A 2007-08-27 2008-08-25 Osmolyte zur behandlung von allergisch bedingten atemwegserkrankungen Active EP2200603B1 (de)

Priority Applications (7)

Application Number Priority Date Filing Date Title
PL08801690T PL2200603T3 (pl) 2007-08-27 2008-08-25 Osmolity do leczenia alergicznych chorób oddechowych
PL15189573T PL3006022T3 (pl) 2007-08-27 2008-08-25 Osmolity do leczenia wirusowych chorób układu oddechowego
EP15189573.7A EP3006022B1 (de) 2007-08-27 2008-08-25 Osmolyte zur behandlung von viral bedingten atemwegserkrankungen
PL11004754T PL2380569T3 (pl) 2007-08-27 2008-08-25 Osmolity do zmniejszania niepożądanych działań steroidów lub leków przeciwhistaminowych
DK11004754.5T DK2380569T3 (da) 2007-08-27 2008-08-25 Osmolyt til reduktion af bivirkningerne af steroider eller antihistaminika
EP18203610.3A EP3482755A1 (de) 2007-08-27 2008-08-25 Pharmazeutische zusammensetzung, enthaltend mindestens ein kompatibles solut sowie mindestens einen weiteren wirkstoff
EP11004754.5A EP2380569B1 (de) 2007-08-27 2008-08-25 Osmolyte zur Reduzierung der Nebenwirkungen von Steroiden oder Antihistaminika

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007040615A DE102007040615A1 (de) 2007-08-27 2007-08-27 Osmolyte zur Behandlung von allergisch oder viral bedingten Atemwegserkrankungen
PCT/EP2008/006959 WO2009027069A2 (de) 2007-08-27 2008-08-25 Osmolyte zur behandlung von allergisch oder viral bedingten atemwegserkrankungen

Related Child Applications (3)

Application Number Title Priority Date Filing Date
EP15189573.7A Division EP3006022B1 (de) 2007-08-27 2008-08-25 Osmolyte zur behandlung von viral bedingten atemwegserkrankungen
EP18203610.3A Division EP3482755A1 (de) 2007-08-27 2008-08-25 Pharmazeutische zusammensetzung, enthaltend mindestens ein kompatibles solut sowie mindestens einen weiteren wirkstoff
EP11004754.5A Division EP2380569B1 (de) 2007-08-27 2008-08-25 Osmolyte zur Reduzierung der Nebenwirkungen von Steroiden oder Antihistaminika

Publications (2)

Publication Number Publication Date
EP2200603A2 EP2200603A2 (de) 2010-06-30
EP2200603B1 true EP2200603B1 (de) 2011-06-29

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Family Applications (4)

Application Number Title Priority Date Filing Date
EP08801690A Active EP2200603B1 (de) 2007-08-27 2008-08-25 Osmolyte zur behandlung von allergisch bedingten atemwegserkrankungen
EP18203610.3A Withdrawn EP3482755A1 (de) 2007-08-27 2008-08-25 Pharmazeutische zusammensetzung, enthaltend mindestens ein kompatibles solut sowie mindestens einen weiteren wirkstoff
EP11004754.5A Active EP2380569B1 (de) 2007-08-27 2008-08-25 Osmolyte zur Reduzierung der Nebenwirkungen von Steroiden oder Antihistaminika
EP15189573.7A Active EP3006022B1 (de) 2007-08-27 2008-08-25 Osmolyte zur behandlung von viral bedingten atemwegserkrankungen

Family Applications After (3)

Application Number Title Priority Date Filing Date
EP18203610.3A Withdrawn EP3482755A1 (de) 2007-08-27 2008-08-25 Pharmazeutische zusammensetzung, enthaltend mindestens ein kompatibles solut sowie mindestens einen weiteren wirkstoff
EP11004754.5A Active EP2380569B1 (de) 2007-08-27 2008-08-25 Osmolyte zur Reduzierung der Nebenwirkungen von Steroiden oder Antihistaminika
EP15189573.7A Active EP3006022B1 (de) 2007-08-27 2008-08-25 Osmolyte zur behandlung von viral bedingten atemwegserkrankungen

Country Status (15)

Country Link
US (1) US8765691B2 (pl)
EP (4) EP2200603B1 (pl)
JP (1) JP2010536904A (pl)
KR (1) KR101638637B1 (pl)
AT (1) ATE514422T1 (pl)
AU (1) AU2008291302B2 (pl)
CA (2) CA2942021C (pl)
DE (1) DE102007040615A1 (pl)
DK (1) DK2380569T3 (pl)
ES (3) ES2370955T3 (pl)
HU (1) HUE043920T2 (pl)
PL (3) PL2380569T3 (pl)
PT (1) PT2380569T (pl)
TR (1) TR201908270T4 (pl)
WO (1) WO2009027069A2 (pl)

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EP1858519B1 (de) * 2005-03-12 2013-02-20 Bitop Aktiengesellschaft Für Biotechnische Optimierung Ectoin und/oder hydroxyectoin zur prophylaxe und behandlung chronisch entzündlicher darmerkrankungen
DE102008036725B4 (de) * 2008-08-07 2021-01-28 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Pharmazeutische Zusammensetzung für die nasale Applikation
DE102008039231A1 (de) 2008-08-22 2010-02-25 Bitop Ag Verwendung von Glucosylglycerol
DE102011113059A1 (de) * 2011-09-09 2013-03-14 Bitop Ag Therapeutische Anwendungen von Ectoin
CA2856680C (en) 2011-11-24 2020-07-14 Toyo Sugar Refining Co., Ltd. Protective agent for keratoconjunctiva or suppressive agent for keratoconjunctival disorder
DE202014105553U1 (de) * 2014-08-18 2015-08-20 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Cineolhaltige Zusammensetzung für die nasale Applikation
DE102015121050A1 (de) * 2015-12-03 2017-06-08 Bitop Ag Kompatibles Solut oder Solutgemisch zur Verwendung bei der Prävention oder Behandlung von Krankheiten mit Barrieredefekten in Epithelgeweben
DE102016125378A1 (de) * 2016-12-22 2018-06-28 Werner Schmidt Zusammensetzung zur Behandlung von Erkältungskrankheiten

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DE10330768A1 (de) * 2003-07-07 2005-02-24 bitop Aktiengesellschaft für biotechnische Optimierung Verwendung von aus extremophilen Bakterien gewonnenen Osmolyten zur Herstellung von inhalierbaren Arzneimitteln zur Prophylaxe und Behandlung pulmonaler und kardiovaskulärer Erkrankungen, sowie eines Osmolyte als Wirkstoffbestandteil enthaltende Inhalationsvorrichtung
JP4780907B2 (ja) * 2003-09-30 2011-09-28 小林製薬株式会社 催眠剤組成物
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EP1858519B1 (de) 2005-03-12 2013-02-20 Bitop Aktiengesellschaft Für Biotechnische Optimierung Ectoin und/oder hydroxyectoin zur prophylaxe und behandlung chronisch entzündlicher darmerkrankungen
CN100431559C (zh) * 2005-12-08 2008-11-12 王金政 一种治疗感冒的药物及制备方法
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EP3006022A1 (de) 2016-04-13
PL2380569T3 (pl) 2019-09-30
CA2942021C (en) 2020-11-03
WO2009027069A3 (de) 2009-04-30
EP2380569A3 (de) 2012-06-27
CA2698135C (en) 2016-11-08
HUE043920T2 (hu) 2019-09-30
PL2200603T3 (pl) 2011-12-30
EP3482755A1 (de) 2019-05-15
CA2698135A1 (en) 2009-03-05
AU2008291302A1 (en) 2009-03-05
EP2380569A2 (de) 2011-10-26
ATE514422T1 (de) 2011-07-15
US8765691B2 (en) 2014-07-01
DE102007040615A1 (de) 2009-03-05
DK2380569T3 (da) 2019-06-17
CA2942021A1 (en) 2009-03-05
KR20100075435A (ko) 2010-07-02
AU2008291302B2 (en) 2014-03-20
EP3006022B1 (de) 2021-10-13
US20110053896A1 (en) 2011-03-03
EP2380569B1 (de) 2019-03-13
JP2010536904A (ja) 2010-12-02
ES2730106T3 (es) 2019-11-08
TR201908270T4 (tr) 2019-06-21
KR101638637B1 (ko) 2016-07-11
ES2370955T3 (es) 2011-12-26
PL3006022T3 (pl) 2022-03-28
ES2902827T3 (es) 2022-03-30
EP2200603A2 (de) 2010-06-30

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